Wednesday, November 26, 2014

TLR5 ligand flagellin goes anti-viral

We live in an environment filled with all types of bacterial, viral, fungal and parasitic life forms. Some of those life forms actually live permanently with us, on our epithelial surfaces in a symbiotic relationships.

Broadly speaking, body's immune system is divided into two major subsystems: innate and adaptive. Since adaptive immune system (T and B cells) carried an essential receptor diversity sufficient to recognize myriad of antigens, it was assumed that the organisms deficient in adaptive immune system should easily succumb to infections.

However, more recently, the significance and the capability of innate immune system started to be recognized. So any paper that adds new evidence in this direction requires proper appreciation.

A flagellin, TLR5 agonist ligand become a popular science reagent, especially among Emory immunology club members.

First, the authors found that in adult mice, flagellin injection totally prevented RV infection. Surprisingly, this effect was maintained in RAG KO mice which lack functional T and B cells (it would be interesting to know whether oral flagellin can have a protective effect as well).

Second, flagellin was found to have a therapeutic effect too on established RV infection in RAG KO mice.

Flagellin injection also reduced diarrhea intensity in neonatal mice.

As expected, the authors found that TLR5KO, MyD88KO, NLRC4KO and TLR5KO/NLRC4KO abolished partially or fully flagellin's anti-RV effect (for some reason, the authors have used different Y scales to show flagellin's effect in different KO mice. I personally think it is confusing and totally unnecessary).

Additional experiments indicated that DCs played major role in flagellin's effect.

Finally, the authors showed that injections of IL-22/IL-18 (instead of flagellin) into WT, RAG1-KO or neonatal mice eliminated and reduced clinical symptoms of RV infection.

In summary, this paper shows that flagellin signaling via TLR5 (and partially via NLRC4) induces IL-18 and IL-22 secretion that protects mice from RV infection. It appears that IL-22 is secreted by ILC but the source of IL-18 was not defined. In addition, role of IL-12 family (p40KO mice) is not discussed at all. Are they preparing another paper?

Of course, one major limitation of this study is that all these KO mice have different gut flora. It is important to know if flagellin's effect on RV is mediated through endogenous microbiota. Use of germ-free mice would be useful.